This proposal is submitted pursuant to the application for a Mentored Clinical Scientist Development Award by Bradley S. Henson, D.D.S. This award will enable the applicant to complete his graduate education and training in the Oral Health Sciences Ph.D. Program at the University of Michigan School of Dentistry. The objectives of this application are to optimize current animal models of metastasis for head and neck squamous cell carcinoma (HN SCC) and investigate the role of two candidate proteins, rhoC and galanin receptor 2 (GALR2), in the spread of this disease. Last year, in the US alone, there were an estimated 30,200 newly diagnosed cases of oropharyngeal cancer [2]. Limited prognostic predictability and late detection for individual tumors, based on histopathology and existing staging protocols, results in disfiguring and debilitating surgical, chemotherapeutic and radiotherapeutic interventions. A major determinant of prognosis in HN SCC is metastatic transformation. RhoC, a member of the rho family of GTPases, has been implicated in metastatic potential in cancers of the breast and pancreas, and in malignant melanoma. It is likely that the rho GTPase family plays an important role in regulating cell movement during metastatic transformation, by configuring the actin cytoskeleton for motility through the formation of stress fibers. Rho has been shown to be downstream of galanin receptor 2 (GALR2). GALR2 binds galanin, a 30 amino acid neuropeptide, and has been implicated in small cell lung carcinoma. Overexpression or activating mutations of GALR2 may be important in the tumorigenesis of oropharyngeal SCC. Furthermore, mutations or alterations of expression of GA LR2, leading to activation of rhoC in the same tumor cell population may be an important determinant of aggressive, metastatic tumor behavior. The specific hypothesis to be investigated here is that upregulation or an activating mutation of rhoC and/or GALR2 facilitates metastasis of oropharyngeal SCC. In order to begin to address this hypothesis, we propose to: (1) investigate the role of rhoC in oropharyngeal cancer metastasis, (2.) determine whether overexpression or an activating mutation of GALR2, leads to a more aggressive, metastatic tumor phenotype and to determine if this signaling occurs via rho activation, and (3.) optimize current murine models used to study human o ropharyngeal S CC and develop primary and metastatic oral cancer cell lines.